The abuse of methamphetamine (METH) has escalated in recent years and effective treatments to curtail its use are not available. Our preliminary results demonstrate that alpha-lobeline (LOB), a weakly basic lipophilic alkaloid, acts as an antagonist at nicotine receptors. LOB also inhibits the dopamine transporter (DAT) and the vesicular monoamine transporter (VMAT2), but does not inhibit monoamine oxidase (MAO). Moreover, LOB inhibits amphetamine (AMP) evoked dopamine release and METH self-administration in rats. Our preliminary results suggest that the VMAT2 may be an important new therapeutic target for the treatment of METH abuse. MTD, a synthetic derivative of LOB, which unlike JOB, has negligible affinity for nicotinic receptors, and moreover targets DA transporters. Structural analogs of MTD will be evaluated in neurochemical and behavioral assays to develop the structural activity relationships (SARs) for the VMAT2 pharmacophere.